News Beyond Our Pages
Authors: Marc E. Rothenberg, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2020)

Omalizumab, an mAb directed against IgE used to treat allergic disease, induces adverse side effects ranging from local skin inflammation to anaphylaxis. Balbino et al (J Clin Invest 2020 Jan 27; https://doi.org/10.1172/JCI129697) identified that omalizumab and IgE form immune complexes that mediate both cutaneous inflammation and systemic anaphylaxis through activation of Fcγ receptors. Importantly, the authors engineered a mutant version of omalizumab with an altered Fc region that limited Fcγ-mediated adverse reactions without compromising its ability to block IgE-mediated allergic reactions. These results highlight the potential of limiting adverse reactions with omalizumab through the use of altered versions of the drug. We asked senior authors Pierre Bruhns, PhD, from Institut Pasteur in Paris, France, and Laurent L. Reber, PhD, from CHU-Purpan in Toulouse, France, to comment on the study. They write, “The Fc-engineered anti-IgE mAb we developed is equally potent as omalizumab at blocking allergic reactions but does not induce FcγR-mediated inflammation in the animal models we tested. This mAb could thus potentially be used in patients with very high levels of IgE and/or in patients with a history of anaphylaxis or other adverse reactions to omalizumab.”Limited Fcγ-mediated adverse reactions without compromising its ability to block IgE-mediated allergic reactions Limited Fcγ-mediated adverse reactions without compromising its ability to block IgE-mediated allergic reactions Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by gene defects in the components of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex in phagocytic leukocytes and often requires allogeneic bone marrow transplantation. Kohn et al ( Nat Med 2020 Nat Med 2020;26:200-6; https://doi.org/10.1038/s41591-019-0735-5) performed the first human trials of autologous hematopoietic stem cell transplantation after lentiviral gene therapy in CGD. While 2 subjects died within 3 months from pre-existing comorbid conditions, 6 of the surviving 7 subjects exhibited persistent NADPH-oxidase activity in neutrophils at 12 months without clonal expansion. Importantly, the surviving patients did not have new CGD-related infections, and 6 subjects were able to discontinue all prophylactic antibiotics. These findings show that autologous gene therapy is a promising approach for treatment of patients with CGD. We asked authors Donald B. Kohn, MD, from the University of California Los Angeles in Los Angeles, California, and Adrian J. Thrasher, MD, PhD, from Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust in London, United Kingdom, to comment on the study. They write, “This study done by an international collaborative group demonstrates the potential of autologous gene therapy for X-linked CGD to restore neutrophil oxidase function, with no subsequent CGD-type infections afterwards for the 6 patients who achieved stable engraftment of gene-corrected stem cells. The absence of graft-versus-host disease without need for immune suppressive conditioning and post-transplant immune suppression may make this gene therapy approach favorable compared to allogeneic hematopoietic stem cell transplantation, although further definitive studies are needed.”The surviving patients did not have new CGD-related infections The surviving patients did not have new CGD-related infections In order to expand on their promising finding of a protective effect of prenatal supplementation with vitamin D on the development of asthma and recurrent wheeze through the first 3 years of life, Litonjua et al (N Engl J Med 2020;382:525-33; https://doi.org/10.1056/NEJMoa1906137) extended the observation of the children in their trial through the first 6 years of life. As an extension to their previous findings, maternal supplementation alone with vitamin D did not affect rates of asthma and recurrent wheeze at 6 years of life, even after mothers were stratified on the basis of serum 25-hydroxyvitamin D levels during pregnancy. The results of this study demonstrate that the protective effect of vitamin D supplementation on the development of asthma at 3 years of life is not sustained at 6 years of life. We asked first author Augusto A. Litonjua, MD, MPH, from Golisano Children’s Hospital in Rochester, New York, to comment on the study. He writes, “That the effects of prenatal supplementation alone did not sustain the initial observation on asthma and recurrent wheezing suggests that future studies need to look into more specific phenotypes of early-life wheezing and consider effects of postnatal vitamin D supplementation. We saw small effects on airway resistance measures from ages 4 through 6 years, and we are continuing to follow the children with annual lung function testing.”Maternal supplementation alone with vitamin D did not affect rates of asthma and recurrent wheeze at 6 years of life Maternal supplementation alone with vitamin D did not affect rates of asthma and recurrent wheeze at 6 years of life Anti-CD19 chimeric antigen (CAR) T-cell therapy has shown significant clinical efficacy in multiple CD19-expressing B-cell cancers but induces significant toxicity, including cytokine release syndrome, neurotoxicity, and graft-versus-host disease. Liu et al (N Engl J Med 2020;382:545-53; https://doi.org/10.1056/NEJMoa1910607) performed a combined phase 1 and phase 2 trial to assess the safety and efficacy of using anti-CD19 CAR on natural killer (NK) cells instead of T cells in an attempt to minimize adverse events. Complete remission occurred in 7 of 11 subjects with multiple relapsed or refractory CD19-positive cancers. Notably, CAR-NK cell administration did not induce cytokine release syndrome, and infused CAR-NK cells were detectable at low levels for at least 1 year post-treatment. Collectively, findings underscore the potential of CAR-NK cells to induce specific therapeutic immune responses without cytokine release syndrome. Figure attribution: Public Domain at Wikimedia Commons by user Mxpule.CAR-NK cell administration did not induce cytokine release syndrome CAR-NK cell administration did not induce cytokine release syndrome Nasal brush cells are chemosensory epithelial cells that promote innate type 2 immunity through sensing of cellular damage. Ualiyeva et al (Sci Immunol 2020;5(43); https://doi.org/10.1126/sciimmunol.aax7224) utilized genome-wide transcriptional analyses to clarify the poorly understood molecular pathways underlying the specific effector functions of these cells. The authors identified 2 subsets of nasal brush cells with similar gene expression profiles to tracheal brush cells. These nasal brush cells were avid producers of cysteinyl leukotrienes (CysLTs) after sensing the cellular danger signal adenosine triphosphate (ATP) and were required for aeroallergen-induced eosinophilic inflammation. In total, these findings demonstrate that brush cells contribute to innate type 2 immunity through lipid mediator generation in response to local cellular damage. We asked senior authors Nora A. Barrett, MD, and Lora G. Bankova, MD, of Harvard Medical School in Boston, Massachusetts, to comment on the study. They write, “Our study establishes the nasal brush cells as important sensors of the danger signal ATP expanding their sensing capacities beyond the bitter tasting bacterial ligands that they were previously known to recognize. The mold Alternaria and the house dust mite Dermatophagoides pteronyssinus engage an ATP-P2Y2 autocrine feed forward loop in brush cells that leads to generation of CysLTs providing an important link between allergen sensing by epithelial cells and epithelial cell activation.”Nasal brush cells were avid producers of cysteinyl leukotrienesNews items were written by medical writer Jared Travers, MD, PhD. Nasal brush cells were avid producers of cysteinyl leukotrienes News items were written by medical writer Jared Travers, MD, PhD.